The long-term objective of this work is to understand the skin-brain mechanisms of pruritus in health and disease. Pruritus is the most common dermatological symptom and in its chronic form has a profound impact on quality of life. Recent research has shown a central processing of experimentally-induced itch in healthy subjects but this has not been assessed in disease states as of yet. One long-standing enigma of pruritus research relates to the underlying mechanism of the viscous "itch-scratch cycle". Given the well documented role of opioids in addiction and hedonism, the possible peripheral release of these neuropeptides through scratching may not only further augment the perception of pruritus through peripheral and central mechanisms, it may also contribute to the compulsion to continue scratching. The aims of this application are: 1) to identify neural networks responsible for sensory and affective dimensions of chronic itch, 2) to identify neural networks that attenuate the perception of itch in health and disease, and 3) to test the hypothesis that the compulsion to scratch is mediated through the release of dermal opioids. These aims will be investigated with the use of functional MRI (fMRI) employing the emerging technique of arterial spin labeling, psychophysical assessments, itch questionnaires and dermal microdialysis. By identifying neural networks that underlying and attenuate pathological itch, important mechanistic knowledge will be gained ultimately facilitating the development of novel therapies for this unmet medical need. Additionally, this study will provide translational information of utmost importance to the underlying mechanisms of the "itch-scratch cycle". Narrative. This study aims to identify neural networks that underlie and attenuate chronic itch and in doing so, will facilitate the development of novel therapies for this distressing symptom. Additionally, this study will provide translational information of utmost importance to the underlying mechanisms of the "itch-scratch cycle".